Levels of Blood Biomarkers… Shamshirian A. et al. 5

ORIGINAL ARTICLE

Levels of Blood Biomarkers among Patients with in Comparison to Control Group

Amir Shamshirian1,2,9, Reza Alizadeh-Navaei2, Samira Abedi3, Hamed Jafarpour3, Hanieh Fazli3, Samira Hosseini1, Amirhossein Hessami3, Keyvan Karimifar4, Sedighe Yosefi5, Mohammad Zahedi1, Sepideh Motamen6, Atiyeh Ghorbanpour7, Bahman Zarandi7, Aliakbar Esfahani4, Yeganeh Rostamian-Moghaddam8, Shirin Mehdipour9, Keyvan Heydari3, Sedigheh Aghajanian1, Somayeh Pour Mehdi9, Alireza Azad9, Soheil Azizi1,9*

OPEN ACCESS ABSTRACT

Citation: Amir Shamshirian, Reza Alizadeh- Navaei, Samira Abedi. Levels of Blood Biomarkers BACKGROUND: Myocardial infarction (MI) as a term for a among Patients with Myocardial Infarction in heart attack happens due to reduced blood flow to heart Comparison to Control Group. Ethiop J Health Sci. myocardium and lack of oxygen supply caused by plaques in 2020;30(1): 5.doi:http://dx.doi.org/10.4314/ejhs.v30 i1.2 the interior walls of coronary arteries. With respect to the Received: July 08, 2018 importance of MI etiology, we aimed to study the relationship Accepted: July 24, 2019 Published: January 1, 2020 of MI and blood examination variables. Copyright: ©2020 Shamshirian A, et al. This is an METHODS: This study was conducted in Mazandaran Heart open access article distributed under the terms of the Center as a hospital-based case-control Comprising 894 Creative Commons Attribution License, which permits unrestricted use, distribution, and participants including 465 cases and 429 controls, reproduction in any medium, provided the original individually matched by sex and age. Considered blood author and source are credited. Funding: Student Research Committee, markers were analyzed using routine laboratory methods and Mazandaran University of Medical Sciences equipment. Competing Interests: The authors declare that this RESULTS: Of all participants, 64.3% of the cases and 51.0% manuscript was approved by all authors in its form and that no competing interest exists. of the controls were males with a mean age of 61.2 (±13.8) in Affiliation and Correspondence: cases and 62.4 (±14.) in controls. We could not find any 1Department of Medical Laboratory Sciences, differences between cases and controls for total School of Allied Medical sciences, Mazandaran University of Medical Sciences, Iran. (TC), low-density lipoprotein (LDL), high-density lipoprotein 2Gastrointestinal Research Center, (HDL), and alkaline-phosphatase (ALP) (P>0.05). However, Mazandaran University of Medical Sciences, Iran. levels of creatine-kinase-muscle/brain (CK-MB) (P<0.0001), 3Student Research Committee, School of Medicine, Mazandaran University of Medical fasting-blood-sugar (FBS) (P<0.0001), aspartate- Sciences, Iran. aminotransferase (AST) (P<0.0001), alanine-transferase 4Student Research committee, Mashhad University of Medical Sciences, Mashhad, Iran. (ALT) (P<0.0001) and erythrocyte sedimentation rate (ESR) 5Department of Biochemistry, Faculty of (P=0.001) were significantly higher in cases compared to the Medicine, Semnan University of Medical controls (P<0.05). Multivariable analyses revealed that the Sciences, Semnan, Iran. 6Department of Medical Biotechnology, Faculty risk of MI was associated with high levels of AST (adjusted of Medical Sciences, Tarbiat Modares University, OR=24.3, 95%CI=3.5±165.6, P=0.001) and LDL (adjusted Iran. 7Department of Hematology, Student Research OR=7.4, 95%CI=1.0±51.8, P=0.001). Committee, Iran University of Medical Sciences, CONCLUSION: Our investigation indicated that the levels of Iran. CK-MB, FBS, AST, ALT and ESR were significantly higher 8Blood Transfusion Research Center, Mazandaran Blood Transfusion Center, Sari, Iran. in patients with MI. Besides, our findings showed that the 9Mazandaran Heart Center, Mazandaran risk of MI in cases with high levels of AST and LDL was University of Medical Sciences, Iran. about 24 and 7 times more than the control group *Email: [email protected] respectively. KEYWORDS: Cardiovascular Stroke, Heart Attack, Biochemical Markers, Marker, Laboratory Markers

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INTRODUCTION predict the outcome of patients after acute myocardial infarction. Increased serum level of Myocardial infarction (MI) is defined as the alanine transferase (ALT) and aspartate presence of acute myocardial injury detected by aminotransferase (AST) are associated with a higher abnormal cardiac biomarkers in the setting of risk of CV events. ALT and AST can be elevated evidence of acute myocardial ischemia (1). MI due to cardiac failure, and AST can be significantly happens due to reduced blood flow to heart correlated with death (15). Serum alkaline myocardium and lack of oxygen supply caused by phosphatase (ALP) is also a good prognostic factor plaques in the interior walls of coronary arteries (2). in MI patients (16). It is a major cause of death and disability worldwide Since clinical symptoms are not reliable (3). Over 15% of mortalities worldwide happens due enough in the diagnosis of MI and to MI each year (4). According to the global burden (ECG) can show uncertain of disease report 2017, cardiovascular diseases are patterns, serum biochemical markers can be helpful the leading cause of death in Iran with 196.32 in in confirming and diagnosis of MI (17). With 100/000 people (5). There are approximately 3.6 respect to the importance of MI etiology using blood million patients with cardiovascular disease in Iran, biomarkers, we aimed to investigate the relationship and MI is responsible for 46% deaths due to between MI and blood biomarkers in Mazandaran cardiovascular diseases (6). Heart Center. In the clinical aspect, there is quite a number of , hormones, biological substances and other MATERIALS AND METHODS biomarkers derived from blood or urine that can be Study design: In this hospital-based case-control used in diagnosis (7). Since only myocardium study, data were obtained from all patients admitted contains a considerable amount of - to the Mazandaran Heart Center in Sari city for the muscle/brain (CK-MB), measuring CK-MB period of three months during students’ internship in isoenzyme is a good indicator of MI (8). CK-MB this center. This tertiary center is the largest heart appears 4 to 6 hours after the onset of , and center in the north of Iran, and most of the patients it consists nearly 30% of CK in the myocardium (9). referred to this center are Mazandaranis. The study Plasma lipoproteins are risk factors for was conducted from September 2018 to December cardiovascular (CV) events after MI. High levels of 2018 (according to the Persian solar calendar). low-density lipoprotein (LDL) is associated with increased risk of CV and high levels of high-density Study population: Hospitalized patients diagnosed lipoprotein (HDL) associated with decreased risk of with MI based on diagnostic criteria of the European CV. Decreased LDL and variable HDL levels have Society of Cardiology (ESC) and the American been reported after MI and increased risk of in- College of Cardiology (ACC) guidelines (18) hospital mortality was associated with lower LDL entered into our study as cases. Sex- and age- levels (10). matched (± 1 years) seemingly healthy people, Nonspecific tests which indicate inflammation without a history of MI and negative test can be used to diagnose various diseases. The participated in our study as controls. All of the inflammatory response following MI causes an participants were from the same geographic increased erythrocyte sedimentation rate (ESR) background (Mazandaranis). A consent letter was (11). ESR is also a significant predictor of heart obtained from all participants, and no one refused to failure and might be useful for the diagnostic participate in the study. Exclusion criteria were as criterion for coronary heart disease (12). High levels follows: 1) age under 18 years, 2) history of of blood sugar can increase the risk of death and malignancy, 3) pregnant women, 4) insufficient poor outcome in patients with MI, and it is medical record, and 5) participation refusal. associated with increased risk of in-hospital mortality in these patients (13). Fasting Laboratory measurements: After at least eight in early MI could be a marker for hours overnight fasting, blood samples were drawn high-risk individuals (14). Liver markers can also from all participants. Serum levels of CK-MB, fasting blood sugar (FBS), total cholesterol (TC),

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Levels of Blood Biomarkers… Shamshirian A. et al. 7

LDL, HDL, AST, ALT, and ALP were determined occurrence, we used logistic regression model to using the automatic biochemistry analyzer (Hitachi calculate the odds ratio (OR) with 95% confidence 912, Fameco, Japan). Troponin levels were analyzed interval (95% CI). A P-value less than 0.05 was using MINI VIDAS® immunoanalyzer (bioMérieux, considered statistically significant. France). According to Westergren method, whole This study was approved in the Ethical Review blood of the patients was mixed with sodium citrate Committee of the Mazandaran University of in a standardized calibrated tube, which are allowed Medical Science (MAZUMS) with ethical code to sit for 60 minutes in the LENA ESR analyzer to IR.MAZUMS.REC.1398.469. The Student measure the sedimentation level. Research Committee of the MAZUMS sent a request to the Mazandaran Heart Center for Statistical analysis: The Statistical Package for the collaboration. To comply with ethical standards, the Social Sciences 16.0 (SPSS Inc., Chicago, Illinois, consent form was filled out with all participants and USA) was used for data analysis. A descriptive their medical records were used confidentiality, analysis of categorical variables was performed exclusively for the research purpose. using frequencies and percentages. Variables comparisons were calculated using chi-square or RESULTS Fisher exact tests, as appropriate. CK-MB>190, FBS>115, TC>200, LDL>160, HDL<40, AST>35, In total, 894 subjects: 465 cases including 299 ALT>40, ALP>306 and ESR>20 were considered (64.3%) males and 166(35.7%) females and 429 as abnormal levels. Comparisons of cases and controls including 219(51.0%) males and 210 controls regarding study variables were performed (49.0%) females, which matched by sex and age using the unpaired t-test or ANOVA for normally participated in the investigation. The characteristics distributed parameters. In order to evaluate the of the cases and controls are presented in Table 1. interactive effects of study variables on MI

Table 1: Demographical and laboratory characteristics of the cases and controls

Variable Case (n=465) Control (n=429) P-value Sex, male n (%) 299 (64.3) 219 (51.0) matched Age, years* 61.2 ±13.8 62.4 ±14.1 matched CK-MB, IU/L* 108.3 ± 155.6 42.0 ± 88.9 <0.0001 FBS, mg/dL* 131.4 ± 78.4 101.5 ± 44.2 <0.0001 TC, mg/dL* 174.5 ± 49.7 178.8 ± 101.6 0.340 LDL, mg/dL* 150.6 ± 768.8 99.2 ± 42.7 0.103 HDL, mg/dL* 36.6 ± 12.1 36.6 ± 13.0 0.754 ESR, mm/h* 47.0 ± 48.7 28.5 ± 27.3 0.001

CK-MB: creatine kinase-muscle/brain; FBS: Fasting Blood Sugar; TC: Total Cholesterol; LDL: Low-Density Lipoprotein; HDL: High-Density Lipoprotein; AST: Aspartate Aminotransferase; ALT: Alanine ; ALP: ; ESR: Erythrocyte Sedimentation Rate. ∗mean ± SD

The mean age of cases was 61.2 years (±13.8) while (P<0.0001). Regarding liver enzymes, although the mean age of controls was 62.4 years (±14.1). levels of ALP was not different between the two There were no differences between cases and groups, levels of both AST (P<0.0001) and ALT controls regarding TC, LDL, HDL, and ALP. (P<0.0001) were significantly higher in cases than As a cardiac marker, CK-MB levels were higher in controls. Moreover, level of ESR was meaningfully MI patients in comparison to the control group higher in cases (P=0.001). (P<0.0001). The mean amount of FBS was Multivariable analyses revealed that the significantly higher in cases than in controls increase in risk for MI was associated with high

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8 Ethiop J Health Sci. Vol. 30, No. 1 January 2020 levels of AST (adjusted OR=24.3, significant relationships were observed for other 95%CI=3.5±165.6, P=0.001) and LDL (adjusted parameters. Risk estimates were present in Table 2. OR=7.4, 95%CI=1.0±51.8, P=0.001). However, no

Table 2: Associations between considered variables and risk of Myocardial infarction

Variable OR* (95%CI) P-value Sex 0.050 (0.008-0.308) 0.001 Age 0.980 (0.934-1.028) 0.415 CK-MB 0.209 (0.003-15.391) 0.475 FBS 2.365 (0.511-10.948) 0.271 TC 0.566 (0.107-2.990) 0.503 LDL 7.481 (1.080-51.806) 0. 042 HDL 3.629 (0. 757-17.396) 0.107 AST 24.366 (3.583-165.697) 0.001 ALT 0.791 (0.063-9.879) 0.856 ALP 1.857 (0.376-9.166) 0.447 ESR 0.263 (0.043-1.616) 0.149

CK-MB: creatine kinase-muscle/brain; FBS: Fasting Blood Sugar; TC: Total Cholesterol; LDL: Low-Density Lipoprotein; HDL: High-Density Lipoprotein; AST: Aspartate Aminotransferase; ALT: ; ALP: Alkaline phosphatase; ESR: Erythrocyte Sedimentation Rate. *Adjusted by age and sex

Figure 1: Differences between cases and controls regarding liver enzymes

DISCUSSION in patients with MI. Besides, our findings showed that the risk of MI in cases with high levels of AST Our investigation indicated that levels of CK-MB, and LDL was about 24 and 7 times more than the FBS, AST, ALT, and ESR were significantly higher control group respectively.

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Our findings showed that CK-MB levels were factors for MI diagnosis by the year 1979, which significantly higher in cases with MI, and many was altered by the immunoassay’s development in other studies reported the good performance of this 1980 (31,32). in detection of MI (19,20). In contrast, it Regarding lipids profile, our findings showed is also reported that the weak sensitivity and that cases with high levels of LDL are at risk of MI specificity for CK-MB in this regard and its 7 times more than the control group, which is in the accuracy is still controversial, especially after same line with previous studies (33,34). However resuscitation (21). However, it seems that it can be other members of lipids, although we could not find a useful marker along with other diagnostic any relationships, previous studies indicated a approaches for MI detection. relationship between low levels of HDL (35) and Regarding FBS, our results were in the same high levels of (36) and risk of MI. line with the study of Abbasi et al., which However, facts regarding HDL are still considered the high levels of FBS as one of the MI controversial (37). risk factors (22). It is remarkable that the study of Our investigation indicated that high levels of Ishihara et al. showed that hyperglycemia is ESR could be related to poor prognosis of MI, associated with MI and that it can deteriorate the which was previously reported in several studies prognosis in both diabetic and non-diabetic similarly (38,39). Therefore, it seems that ESR can individuals (23). It is also reported that be considered as a prognostic factor for monitoring hyperglycemia is associated with the development of patients with MI to prevent the heart acute of kidney injury and left ventricular dysfunction attacks (40). (because of the no-reflow phenomenon) in patients As a strength of the study, to our knowledge, with MI (24, 25). Hyperglycemia can affect MI there is no investigation regarding the association through several ways such as induction of of blood biomarkers with MI in this extent, at least electrophysiological alterations following in Iran. However, due to the retrospective nature of arrhythmias, ischemic preconditioning, coagulation the study as a limitation, it is recommended that a alteration, which likely to increase thrombosis comprehensive longitudinal cohort study be activation, inflammatory amplification, and designed in order to examine the accurate role of inducing endothelial dysfunction (26). these markers in MI. Among liver enzymes, levels of AST and ALT In conclusion, we found that levels of CK-MB, were elevated in MI patients significantly in FBS, AST, ALT, and ESR were significantly higher comparison to the control group, which was also in patients with MI compared to the control group. reported in the study of Lofthus et al. (27). About Besides, our results indicated that individuals with ALP, although we did not find any relationships high levels of AST were at risk of MI about 24 with MI, Nunes et al. found that high levels of ALP times more than the control group. Moreover, this can act as a diagnostic factor for decreased survival risk was also 7 times higher in cases with high rate and renal function in male diabetic patients levels of LDL. Hence, clinicians may consider these with MI (28). factors as a valuable diagnostic or prognostic factor Besides, our check results showed that the for patients with MI to prevent the next attacks and probability of MI in individuals with high levels of for a healthy population to prevent the first attack. AST is nearly 17 times more than the control group. Nevertheless, more comprehensive studies in This was one of the first cardiac biomarkers different regions need to be done to avoid the used in the year 1954, and because of weak geographical and race biases, which may affect the specificity for the matter, it is no longer used as a matter. gold standard. Thereafter, total creatine kinase level and were used as a diagnostic factor for MI by the years 1959 and 1960 respectively (29,30). Eventually, the World Health Organization (WHO) suggested using these three

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ACKNOWLEDGMENTS Myocardial Infarction (The Lipid Paradox). Am J Cardiol. 2015;115(5):557-62. The authors would like to express their gratitude to 11. Boltax AJ, Fischel EE. Serologic tests for the Student Research Committee of Mazandaran inflammation: Serum complement, C-reactive University of Medical Sciences for supporting this protein and erythrocyte sedimentation rate in project with the code 4783 on March 5, 2019. We myocardial infarction. Am J Med. also appreciate the cooperation of staff working at 1956;20(3):418-27. Mazandaran Heart Center. 12. Yayan J. Erythrocyte sedimentation rate as a

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